Several lines of evidence converge to indicate that dopamine receptors, particularly the D-2 receptor, are important in the treatment and possibly in the pathogenesis of Tourette Syndrome. These lines of evidence derive from the observations that the motor symptoms of TS are ameliorated by D-2 receptor antagonists as effectively as by combined D-1 and D-2 antagonists. However, increasing evidence supports a role of D-1 receptors in the control of movement and in neuroleptic efficacy. Dopamine receptors exist as two distinct-subtypes in the central nervous system. D-1 receptors mediate the stimulation of adenylate cyclase, while D-2 receptor activation inhibits adenylate cyclase activity. The density of both D-1 and D-2 receptors is high in the basal ganglia, limbic forebrain and regions of the cortex. The molecular structure of the D-2 receptor has recently been determined and has been found to be similar to other G protein-linked receptors. The goal of this project is to obtain, by molecular cloning techniques, the rat D-1 receptor cDNA and to express the D-1 receptor in eukaryotic cell lines. A better understanding of the molecular mechanisms of both the acute and long-term motor effects of neuroleptic drugs awaits the development of more selective D-1 agonists and antagonists. Development of more effective D-1 antagonists and their concurrent use with D-2 antagonists may more effectively ameliorate the motor and behavioral symptoms of TS (perhaps with fewer dose-limiting side effects). Greater insight into D-1 and D-2 receptor interaction at the cellular level will be facilitated by obtaining the D-1 receptor molecule and expressing it (together with D-2 receptor) at high levels in eukaryotic cell lines. A structural analysis of the D-1 receptor will facilitate more rational design of D-1 antagonists and agonists, which may provide more effective control of the symptoms of TS and insight into the pathophysiologic mechanisms of TS. J. Stephen Fink, M.D., Ph.D. Harvard Medical School, Cambridge, MA Award: $25,000* *Dr. Martin Kelin TS Research Memorial Fund Tourette Association of America Inc. – Research Grant Award 1989